Written by Peter Liu
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Atrasentan is a new selective endothelin type A receptor (ETAR) antagonist that reduces proteinuria for patients with IgA nephropathy in the ALIGN RCT. Long-term CKD outcomes are pending.
Endothelin receptor inhibition promising but unproven
IgA nephropathy is the most frequent cause of primary glomerulonephritis, but to date, there are no established disease-specific medical therapies, and the mainstay of medical care relies on angiotensin-receptor blockers (ARB) and SGLT2 inhibitors. Today’s featured study reports on interim outcomes of ALIGN, an ongoing phase 3, multinational, double-blind, randomized controlled trial assessing whether the study drug atrasentan reduces proteinuria and improves outcomes in patients with IgA nephropathy. Among 270 patients, atrasentan led to a 38.1% reduction in the urinary protein-to-creatinine ratio from baseline versus 3.1% with placebo, yielding a significant between-group difference of -36.1 percentage points (95%CI -44.6 to -26.4; P<0.001). Adverse events were comparable between groups. These findings from ALIGN are similar to those from the PROTECT RCT on sparsentan (a dual ETAR and angiotensin type 1 receptor antagonist). Despite sparsentan’s similar beneficial effect on proteinuria, it ultimately did not show substantial improvements in renal failure outcomes over 2 years. Therefore, the appropriateness of sparsentan in IgA nephropathy remains questionable. The forthcoming 136-week follow-up outcomes of ALIGN will hopefully reveal robust clinical outcomes for atrasentan, because concomitant ARB therapy is possible with the more selective ETAR inhibition of atrasentan, whereas it is contraindicated in sparsentan. Atrasentan now has evidence of positive effect in both diabetic nephropathy with proteinuria (SONAR trial) and in IgA nephropathy. We may see its use increase in the coming years, pending further clinical trial data.
How does this change my practice?
Atrasentan prescribing and monitoring will probably be limited to specialists that are trained to manage this medication (atrasentan has hepatotoxic and teratogenic properties, similar to sparsentan, that will likely require a risk evaluation and mitigation strategy, or REMS). However, it is important to know of this disease-specific treatment for IgA nephropathy and to refer patients with IgA nephropathy to proper specialists that can consider use of this therapy.
Source
Atrasentan in Patients with IgA Nephropathy. N Engl J Med. 2025 Feb 6;392(6):544-554. doi: 10.1056/NEJMoa2409415. Epub 2024 Oct 25. PMID: 39460694
